scholarly journals Single-cell resolution unravels spatial alterations in metabolism, transcriptome and epigenome of ageing liver

2021 ◽  
Author(s):  
Chrysa Nikopoulou ◽  
Niklas Kleinenkuhnen ◽  
Swati Parekh ◽  
Tonantzi Sandoval ◽  
Farina Schneider ◽  
...  
Keyword(s):  
Single Cell ◽  
Lipid Droplets ◽  
Rna Seq ◽  
Epigenetic Landscape ◽  
Functional Differences ◽  
Age Related ◽  
Metabolic States ◽  
Murine Liver ◽  
Transcriptional Changes ◽  
Age Related Changes

Epigenetic ageing clocks have revealed that tissues within an organism can age with different velocity. However, it has not been explored whether cells of one type experience different ageing trajectories within a tissue depending on their location. Here, we employed lipidomics, spatial transcriptomics and single-cell ATAC-seq in conjunction with available single-cell RNA-seq data to address how cells in the murine liver are affected by age-related changes of the microenvironment. Integration of the datasets revealed zonation-specific and age-related changes in metabolic states, the epigenome and transcriptome. Particularly periportal hepatocytes were characterized by decreased mitochondrial function and strong alterations in the epigenetic landscape, while pericentral hepatocytes,despite accumulation of large lipid droplets, did not show apparent functional differences. In general, chromatin alterations did not correlate well with transcriptional changes, hinting at post-transcriptional processes that shape gene expression during ageing. Together, we provide evidence that changing microenvironments within a tissue exert strong influences on their resident cells that can shape epigenetic, metabolic and phenotypic outputs.

scholarly journals Age-related changes of gene expression in the neocortex: Preliminary data on RNA-Seq of the transcriptome in three functionally distinct cortical areas

2012 ◽  
Vol 24 (4) ◽  
pp. 1427-1442 ◽  
Author(s):  
Oksana Yu. Naumova ◽  
Dean Palejev ◽  
Natalia V. Vlasova ◽  
Maria Lee ◽  
Sergei Yu. Rychkov ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Rna Seq ◽  
Signaling Systems ◽  
Cortical Areas ◽  
Age Related ◽  
Transcriptional Changes ◽  
Atypical Development ◽  
The Brain ◽  
Age Related Changes

AbstractThe study of gene expression (i.e., the study of the transcriptome) in different cells and tissues allows us to understand the molecular mechanisms of their differentiation, development and functioning. In this article, we describe some studies of gene-expression profiling for the purposes of understanding developmental (age-related) changes in the brain using different technologies (e.g., DNA-Microarray) and the new and increasingly popular RNA-Seq. We focus on advancements in studies of gene expression in the human brain, which have provided data on the structure and age-related variability of the transcriptome in the brain. We present data on RNA-Seq of the transcriptome in three distinct areas of the neocortex from different ages: mature and elderly individuals. We report that most age-related transcriptional changes affect cellular signaling systems, and, as a result, the transmission of nerve impulses. In general, the results demonstrate the high potential of RNA-Seq for the study of distinctive features of gene expression among cortical areas and the changes in expression through normal and atypical development of the central nervous system.

scholarly journals Integrated analyses of the single-cell ATAC-seq and RNA-seq reveal the epigenetic landscape of human ovarian aging

2021 ◽  
Author(s):  
Yunzhao Xu ◽  
Jinling Chen ◽  
Shuting Gu ◽  
Yuanlin Liu ◽  
Huihua Ni ◽  
...  
Keyword(s):  
Single Cell ◽  
Molecular Mechanisms ◽  
Integrated Analysis ◽  
Age Difference ◽  
Rna Seq ◽  
Epigenetic Landscape ◽  
Operating Characteristics ◽  
Ovarian Aging ◽  
Age Related ◽  
Oocyte Aging

Studying the molecular mechanisms of ovarian aging is crucial for understanding the age-related fertility issues in females. Recently, a single-cell transcriptomic roadmap of ovarian aging based on non-human primates revealed the molecular signatures of the oocytes at different developmental stages. Herein, we present the first epigenetic landscape of human ovarian aging, through an integrated analysis of the single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) and single-cell RNA-seq. We depicted the transcriptional profiles and chromatin accessibility of the ovarian tissues isolated from old (n=4) and young (n=2) donors. The unsupervised clustering of data revealed seven distinct cell populations in the ovarian tissues and six subtypes of oocytes, which could be distinguished by age difference. Further analysis of the scATAC-seq data from the young and old oocytes revealed that the interaction between the Notch signaling pathway and AP-1 family transcription factors may crucially determine oocyte aging. Finally, a machine-learning algorithm was applied to calculate the optimal model based on the single-cell dataset for predicting oocyte aging, which exhibited excellent accuracy with a cross-validated area under the receiver operating characteristics score of 0.99. In summary, this study provides a comprehensive understanding of human ovarian aging at both the transcriptomic and epigenetic levels, based on an integrated analysis of large-scale single-cell datasets. We believe our results will shed light on the discovery of potential therapeutic targets or diagnostic markers for age-related ovarian disorders.

scholarly journals Integrated analyses of the single-cell ATAC-seq and RNA-seq reveal the epigenetic landscape of human ovarian aging

2022 ◽  
Author(s):  
Yunzhao Xu ◽  
Jinling Chen ◽  
Shuting Gu ◽  
Yuanlin Liu ◽  
Huihua Ni ◽  
...  
Keyword(s):  
Single Cell ◽  
Molecular Mechanisms ◽  
Integrated Analysis ◽  
Age Difference ◽  
Rna Seq ◽  
Epigenetic Landscape ◽  
Operating Characteristics ◽  
Ovarian Aging ◽  
Age Related ◽  
Oocyte Aging

Abstract Studying the molecular mechanisms of ovarian aging is crucial for understanding the age-related fertility issues in females. Recently, a single-cell transcriptomic roadmap of ovarian aging based on non-human primates revealed the molecular signatures of the oocytes at different developmental stages. Herein, we present the first epigenetic landscape of human ovarian aging, through an integrated analysis of the single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) and single-cell RNA-seq. We depicted the transcriptional profiles and chromatin accessibility of the ovarian tissues isolated from old (n=4) and young (n=2) donors. The unsupervised clustering of data revealed seven distinct cell populations in the ovarian tissues and six subtypes of oocytes, which could be distinguished by age difference. Further analysis of the scATAC-seq data from the young and old oocytes revealed that the interaction between the Notch signaling pathway and AP-1 family transcription factors may crucially determine oocyte aging. Finally, a machine-learning algorithm was applied to calculate the optimal model based on the single-cell dataset for predicting oocyte aging, which exhibited excellent accuracy with a cross-validated area under the receiver operating characteristics score of 0.99. In summary, this study provides a comprehensive understanding of human ovarian aging at both the transcriptomic and epigenetic levels, based on an integrated analysis of large-scale single-cell datasets. We believe our results will shed light on the discovery of potential therapeutic targets or diagnostic markers for age-related ovarian disorders.

scholarly journals Single-Cell Transcriptomics Reveals the Expression of Aging- and Senescence-Associated Genes in Distinct Cancer Cell Populations

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3126
Author(s):  
Dominik Saul ◽  
Robyn Laura Kosinsky
Keyword(s):  
Single Cell ◽  
Myelogenous Leukemia ◽  
Ductal Adenocarcinoma ◽  
Cell Populations ◽  
Rna Seq ◽  
Healthy Control ◽  
Transcriptional Changes ◽  
The Relationship ◽  
Senescence Associated Genes

The human aging process is associated with molecular changes and cellular degeneration, resulting in a significant increase in cancer incidence with age. Despite their potential correlation, the relationship between cancer- and ageing-related transcriptional changes is largely unknown. In this study, we aimed to analyze aging-associated transcriptional patterns in publicly available bulk mRNA-seq and single-cell RNA-seq (scRNA-seq) datasets for chronic myelogenous leukemia (CML), colorectal cancer (CRC), hepatocellular carcinoma (HCC), lung cancer (LC), and pancreatic ductal adenocarcinoma (PDAC). Indeed, we detected that various aging/senescence-induced genes (ASIGs) were upregulated in malignant diseases compared to healthy control samples. To elucidate the importance of ASIGs during cell development, pseudotime analyses were performed, which revealed a late enrichment of distinct cancer-specific ASIG signatures. Notably, we were able to demonstrate that all cancer entities analyzed in this study comprised cell populations expressing ASIGs. While only minor correlations were detected between ASIGs and transcriptome-wide changes in PDAC, a high proportion of ASIGs was induced in CML, CRC, HCC, and LC samples. These unique cellular subpopulations could serve as a basis for future studies on the role of aging and senescence in human malignancies.

scholarly journals CRT-600.10 Quantitative Analysis Of Aging Based On Age−related Changes In Electrical Impedance Of Single Cell

2017 ◽  
Vol 10 (3) ◽  
pp. S54-S55
Author(s):  
Jung-Joon Cha ◽  
Yangkyu Park ◽  
Joho Yun ◽  
Juhun Lim ◽  
Sang-Jin Lee ◽  
...  
Keyword(s):  
Quantitative Analysis ◽  
Single Cell ◽  
Electrical Impedance ◽  
Age Related ◽  
Age Related Changes

scholarly journals Single-Cell RNA-Seq of Cisplatin-Treated Adult Stria Vascularis Identifies Cell Type-Specific Regulatory Networks and Novel Therapeutic Gene Targets

2021 ◽  
Vol 14 ◽  
Author(s):  
Ian A. Taukulis ◽  
Rafal T. Olszewski ◽  
Soumya Korrapati ◽  
Katharine A. Fernandez ◽  
Erich T. Boger ◽  
...  
Keyword(s):  
Single Cell ◽  
Regulatory Networks ◽  
Stria Vascularis ◽  
Cell Types ◽  
Cellular Level ◽  
Transcriptional Analysis ◽  
Rna Seq ◽  
Transcriptional Responses ◽  
Transcriptional Changes ◽  
Cell Type Specific

The endocochlear potential (EP) generated by the stria vascularis (SV) is necessary for hair cell mechanotransduction in the mammalian cochlea. We sought to create a model of EP dysfunction for the purposes of transcriptional analysis and treatment testing. By administering a single dose of cisplatin, a commonly prescribed cancer treatment drug with ototoxic side effects, to the adult mouse, we acutely disrupt EP generation. By combining these data with single cell RNA-sequencing findings, we identify transcriptional changes induced by cisplatin exposure, and by extension transcriptional changes accompanying EP reduction, in the major cell types of the SV. We use these data to identify gene regulatory networks unique to cisplatin treated SV, as well as the differentially expressed and druggable gene targets within those networks. Our results reconstruct transcriptional responses that occur in gene expression on the cellular level while identifying possible targets for interventions not only in cisplatin ototoxicity but also in EP dysfunction.

scholarly journals Epigenetic Control of Haematopoietic Stem Cell Aging and Its Clinical Implications

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Fizzah Aziz Choudry ◽  
Mattia Frontini
Keyword(s):  
Stem Cell ◽  
Chronic Inflammation ◽  
Haematopoietic Stem Cell ◽  
Cell Aging ◽  
Clinical Implications ◽  
Epigenetic Landscape ◽  
Epigenetic Control ◽  
Age Related ◽  
Stem Cell Aging ◽  
Age Related Changes

Aging, chronic inflammation, and environmental insults play an important role in a number of disease processes through alterations of the epigenome. In this review we explore how age-related changes in the epigenetic landscape can affect heterogeneity within the haematopoietic stem cell (HSC) compartment and the deriving clinical implications.

scholarly journals Dynamic changes in the regulatory T-cell heterogeneity and function by murine IL-2 mutein

2020 ◽  
Vol 3 (5) ◽  
pp. e201900520 ◽  
Author(s):  
Daniel R Lu ◽  
Hao Wu ◽  
Ian Driver ◽  
Sarah Ingersoll ◽  
Sue Sohn ◽  
...  
Keyword(s):  
Single Cell ◽  
Single Cell Analysis ◽  
Expression Profiles ◽  
Control Cell ◽  
Mutant Form ◽  
Rna Seq ◽  
Dynamic Changes ◽  
Cell Clustering ◽  
Transcriptional Changes ◽  
And Function

The therapeutic expansion of Foxp3+ regulatory T cells (Tregs) shows promise for treating autoimmune and inflammatory disorders. Yet, how this treatment affects the heterogeneity and function of Tregs is not clear. Using single-cell RNA-seq analysis, we characterized 31,908 Tregs from the mice treated with a half-life extended mutant form of murine IL-2 (IL-2 mutein, IL-2M) that preferentially expanded Tregs, or mouse IgG Fc as a control. Cell clustering analysis revealed that IL-2M specifically expands multiple sub-states of Tregs with distinct expression profiles. TCR profiling with single-cell analysis uncovered Treg migration across tissues and transcriptional changes between clonally related Tregs after IL-2M treatment. Finally, we identified IL-2M–expanded Tnfrsf9+Il1rl1+ Tregs with superior suppressive function, highlighting the potential of IL-2M to expand highly suppressive Foxp3+ Tregs.

scholarly journals Quantifying Waddington’s epigenetic landscape: a comparison of single-cell potency measures

2018 ◽  
Author(s):  
Jifan Shi ◽  
Andrew E. Teschendorff ◽  
Weiyan Chen ◽  
Luonan Chen ◽  
Tiejun Li
Keyword(s):  
Single Cell ◽  
Cell Fate ◽  
Chain Process ◽  
Rna Seq ◽  
Epigenetic Landscape ◽  
Energy Potential ◽  
Biophysical Models ◽  
Level Information ◽  
Cell Phenotypes ◽  
Orthogonal Systems

Over 60 years ago Waddington proposed an epigenetic landscape model of cellular differentiation, whereby cell-fate transitions are modelled as canalization events, with stable cell states occupying the basins or attractor states1, 2. A key ingredient of this landscape is the energy potential, or height3, which correlates with cell-potency. To date, very few explicit biophysical models for estimating single-cell potency have been proposed. Using 9 independent experiments, encompassing over 6,600 high-quality single-cell RNA-Seq profiles, we here demonstrate that single-cell potency can be approximated as the graph entropy of a Markov Chain process on a model signaling network. Our analysis highlights that other proposed single-cell potency measures are not robust, whilst also revealing that integration with orthogonal systems-level information improves potency estimates. Thus, this study provides a foundation for an improved systems-level understanding of single-cell potency, which may have profound implications for the discovery of novel stem-and progenitor cell phenotypes.

scholarly journals Age-related changes to macrophages are detrimental to fracture healing

2019 ◽  
Author(s):  
Daniel Clark ◽  
Sloane Brazina ◽  
Frank Yang ◽  
Diane Hu ◽  
Erene Niemi ◽  
...  
Keyword(s):  
Fracture Healing ◽  
The Elderly ◽  
Fracture Site ◽  
Rna Seq ◽  
Fracture Callus ◽  
Age Related ◽  
The Impact ◽  
Old Mice ◽  
Age Related Changes ◽  
Young Mice

AbstractThe elderly population suffers from higher rates of complications during fracture healing that result in increased morbidity and mortality. Inflammatory dysregulation is associated with increased age and is a contributing factor to the myriad of age-related diseases. Therefore, we investigated age-related changes to an important cellular regulator of inflammation, the macrophage, and the impact on fracture healing outcomes. We demonstrated that old mice (24 months) have delayed fracture healing with significantly less bone and more cartilage compared to young mice (3 months). The quantity of infiltrating macrophages into the fracture callus was similar in old and young mice. However, RNA-seq analysis demonstrated distinct differences in the transcriptomes of macrophages derived from the fracture callus of old and young mice, with an upregulation of M1/pro-inflammatory genes in macrophages from old mice as well as dysregulation of other immune-related genes. Preventing infiltration of the fracture site by macrophages in old mice improved healing outcomes, with significantly more bone in the calluses of treated mice compared to age-matched controls. After preventing infiltration by macrophages, the macrophages within the fracture callus were collected and examined via RNA-seq analysis, and their transcriptome resembled macrophages from young calluses. Taken together, infiltrating macrophages from old mice demonstrate detrimental age-related changes, and depleting infiltrating macrophages can improve fracture healing in old mice.

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